HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use DOXORUBICIN HYDROCHLORIDELIPOSOME INJECTION safely and effectively. See full prescribing information for DOXORUBICIN HYDROCHLORIDELIPOSOME INJECTION.DOXORUBICIN HYDROCHLORIDE liposome injection, for intravenous useInitial U.S. Approval: 1995

WARNING: CARDIOMYOPATHY and INFUSION-RELATED REACTIONS

See full prescribing information for complete boxed warning.

Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m2. Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride, during treatment, and after treatment (5.1).

After failure of prior systemic chemotherapy or intolerance to such therapy. (1.2)

• Multiple Myeloma

In combination with bortezomib in patients who have not previously received bortezomib and have received at least one prior therapy.Doxorubicin hydrochloride is an anthracycline topoisomerase inhibitor indicated for: (1.3)

DOSAGE AND ADMINISTRATION

Administer doxorubicin hydrochloride liposome injection at an initial rate of 1 mg/min to minimize the risk of infusion reactions. If no infusion related reactions occur, increase rate of infusion to complete administration over 1 hour. Do not administer as bolus injection or undiluted solution (2).

Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

WARNING:CARDIOMYOPATHY and INFUSION-RELATED REACTIONS

Doxorubicin hydrochloride liposome injection can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2to 550 mg/m2. Assess left ventricular cardiac function prior to initiation of doxorubicin hydrochloride liposome injection and during and after treatment [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

1.1 Ovarian Cancer

Doxorubicin hydrochloride liposome injection is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy.

1.2 AIDS-Related Kaposi’s Sarcoma

Doxorubicin hydrochloride liposome injection is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy.

1.3 Multiple Myeloma

Doxorubicin hydrochloride liposome injection, in combination with bortezomib, is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy.

2 DOSAGE AND ADMINISTRATION

2.1 Important Use Information

Do not substitute doxorubicin hydrochloride liposome injection for other doxorubicin hydrochloride products.

Do not administer as an undiluted suspension or as an intravenous bolus [see Warnings and Precautions (5.2)].

2.2 Ovarian Cancer

The recommended dose of doxorubicin hydrochloride liposome injection is 50 mg/m2intravenously over 60 minutes every 28 days until disease progression or unacceptable toxicity.

2.3 AIDS-Related Kaposi’s Sarcoma

The recommended dose of doxorubicin hydrochloride liposome injection is 20 mg/m2intravenously over 60 minutes every 21 days until disease progression or unacceptable toxicity.

2.4 Multiple Myeloma

The recommended dose of doxorubicin hydrochloride liposome injection is 30 mg/m2intravenously over 60 minutes on day 4 of each 21-day cycle for eight cycles or until disease progression or unacceptable toxicity. Administer doxorubicin hydrochloride liposome injection after bortezomib on day 4 of each cycle [see Clinical Studies (14.3)].

2.5 Dose Modifications for Adverse Reactions

Do not increase doxorubicin hydrochloride liposome injection after a dose reduction for toxicity.

• Delay dosing up to 2 weeks or until resolved to Grade 0-1, then decrease dose by 25%.•Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks.

Grade 4: Diffuse or local process causing infectious complications, or a bed ridden state or hospitalization

• Delay dosing up to 2 weeks or until resolved to Grade 0-1, then decrease dose by 25%. •Discontinue doxorubicin hydrochloride liposome injection if no resolution after 2 weeks.

Stomatitis

Grade 1: Painless ulcers, erythema, or mild soreness

• If no previous Grade 3 or 4 toxicity: no dose adjustment. If previous Grade 3 or 4 toxicity: delay up to 2 weeks then decrease dose by 25%.

Grade 2: Painful erythema, edema, or ulcers, but can eat

• Delay dosing up to 2 weeks or until resolved to Grade 0-1. • Discontinue doxorubicin hydrochloride liposome injection if there is no resolution after 2 weeks.• If resolved to Grade 0-1 within 2 weeks: o And no previous Grade 3 or 4 stomatitis: resume treatment at previous dose. o And previous Grade 3 or 4 toxicity: decrease dose by 25%.

Grade 3: Painful erythema, edema, or ulcers, and cannot eat

• Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. • If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection.

Grade 4: Requires parenteral or enteral support

• Delay dosing up to 2 weeks or until resolved to Grade 0-1. Decrease dose by 25% and return to original dose interval. If after 2 weeks there is no resolution, discontinue doxorubicin hydrochloride liposome injection.

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if a precipitate or foreign matter is present.

Do not use with in-line filters.

Administer the first dose of doxorubicin hydrochloride liposome injection at an initial rate of 1 mg/min. If no infusion-related adverse reactions are observed, increase the infusion rate to complete the administration of the drug over one hour [see Warnings and Precautions (5.2)].

Do not rapidly flush the infusion line. Do not mix doxorubicin hydrochloride liposome injection with other drugs.

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

Doxorubicin hydrochloride liposome injection is contraindicated in patients who have a history of severe hypersensitivity reactions, including anaphylaxis, to doxorubicin hydrochloride [see Warnings and Precautions (5.2)].

5 WARNINGS AND PRECAUTIONS

5.1 Cardiomyopathy

Doxorubicin hydrochloride can cause myocardial damage, including acute left ventricular failure. The risk of cardiomyopathy with doxorubicin hydrochloride is generally proportional to the cumulative exposure. Include prior use of other anthracyclines or anthracenediones in calculations of cumulative dose. The risk of cardiomyopathy may be increased at lower cumulative doses in patients with prior mediastinal irradiation.

In a clinical study in 250 patients with advanced cancer who were treated with doxorubicin hydrochloride liposome injection, the risk of cardiomyopathy was 11% when the cumulative anthracycline dose was between 450 mg/m2 to 550 mg/m2. Cardiomyopathy was defined as >20% decrease in resting left ventricular ejection fraction (LVEF) from baseline where LVEF remained in the normal range or a >10% decrease in LVEF from baseline where LVEF was less than the institutional lower limit of normal. Two percent of patients developed signs and symptoms of congestive heart failure without documented evidence of cardiomyopathy.

Assess left ventricular cardiac function (e.g. MUGA or echocardiogram) prior to initiation of doxorubicin hydrochloride liposome injection, during treatment to detect acute changes, and after treatment to detect delayed cardiomyopathy. Administer doxorubicin hydrochloride liposome injection to patients with a history of cardiovascular disease only when the potential benefit of treatment outweighs the risk.

5.2 Infusion-Related Reactions

Serious, life-threatening, and fatal infusion-related reactions characterized by one or more of the following symptoms can occur with doxorubicin hydrochloride liposome injection: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. Of 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection in Trial 4, 7% of patients experienced acute infusion-related reactions resulting in dose interruption. All occurred during cycle 1 and none during subsequent cycles. Across multiple studies of doxorubicin hydrochloride liposome injection monotherapy including this and other studies enrolling 760 patients with various solid tumors, 11% of patients had infusion-related reactions. The majority of infusion-related events occurred during the first infusion.

5.3 Hand-Foot Syndrome (HFS)

In Trial 4, the incidence of HFS was 51% of patients in the doxorubicin hydrochloride liposome injection arm and 0.9% of patients in the topotecan arm, including 24% Grade 3 or 4 cases of HFS in doxorubicin hydrochloride liposome injection-treated patients and no Grade 3 or 4 cases in topotecan-treated patients. HFS or other skin toxicity required discontinuation of doxorubicin hydrochloride liposome injection in 4.2% of patients.

HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. Delay doxorubicin hydrochloride liposome injection for the first episode of Grade 2 or greater HFS [see Dosage and Administration (2.5)]. Discontinue doxorubicin hydrochloride liposome injection if HFS is severe and debilitating.

5.4 Secondary Oral Neoplasms

Secondary oral cancers, primarily squamous cell carcinoma, have been reported from post-marketing experience in patients with long-term (more than one year) exposure to doxorubicin hydrochloride liposome injection. These malignancies were diagnosed both during treatment with doxorubicin hydrochloride liposome injection and up to 6 years after the last dose. Examine patients at regular intervals for the presence of oral ulceration or with any oral discomfort that may be indicative of secondary oral cancer.

The altered pharmacokinetics and preferential tissue distribution of liposomal doxorubicin that contributes to enhanced skin toxicity and mucositis compared to free doxorubicin may play a role in the development of oral secondary malignancies with long-term use.

5.5 Embryo-Fetal Toxicity

Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. At doses approximately 0.12 times the recommended clinical dose, doxorubicin hydrochloride liposome injection was embryotoxic and abortifacient in rabbits. Advise pregnant women of the potential risk to a fetus. Advise females and males of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection . [see Use in Specific Populations (8.1) and (8.3)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice.

The safety data described below are from Trial 4, which included 239 patients with ovarian cancer treated with doxorubicin hydrochloride liposome injection 50 mg/m2once every 4 weeks for a minimum of four courses in a randomized, multicenter, open-label study. In this trial, patients received doxorubicin hydrochloride liposome injection for a median number of 3.2 months (range 1 day to 25.8 months). The median age of the patients is 60 years (range 27 to 87), with 91% Caucasian, 6% Black, and 3% Hispanic or Other. Table 3 presents the hematologic adverse reactions from Trial 4.

Table 3: Hematologic Adverse Reactions in Trial 4

Doxorubicin Hydrochloride Liposome Injection Patients(n=239)

Topotecan Patients (n=235)

Neutropenia 500 -<1000/mm3

8%

14%

<500/mm3

4.2%

62%

Anemia 6.5 -<8 g/dL

5%

25%

< 6.5 g/dL

0.4%

4.3%

Thrombocytopenia10,000 -<50,000/mm3

1.3%

17%

<10,000/mm3

0%

17%

Table 4 presents the non-hematologic adverse reactions from Trial 4.

Table 4: Non-Hematologic Adverse Reactions in Trial 4

Non-Hematologic Adverse Reaction 10% or Greater

Doxorubicin Hydrochloride Liposome Injection (%) treated (n=239)

Topotecan (%) treated (n=235)

All grades

Grades 3–4

All grades

Grades 3–4

Body as a Whole

Asthenia

40

7

52

8

Fever

21

0.8

31

6

Mucous Membrane Disorder

14

3.8

3.4

0

Back Pain

12

1.7

10

0.9

Infection

12

2.1

6

0.9

Headache

11

0.8

15

0

Digestive

Nausea

46

5

63

8

Stomatitis

41

8

15

0.4

Vomiting

33

8

44

10

Diarrhea

21

2.5

35

4.2

Anorexia

20

2.5

22

1.3

Dyspepsia

12

0.8

14

0

Nervous

Dizziness

4.2

0

10

0

Respiratory

Pharyngitis

16

0

18

0.4

Dyspnea

15

4.1

23

4.3

Cough increased

10

0

12

0

Skin and Appendages

Hand-foot syndrome

51

24

0.9

0

Rash

29

4.2

12

0.4

Alopecia

19

N/A

52

N/A

The following additional adverse reactions were observed in patients with ovarian cancer with doses administered every four weeks (Trial 4).

Patients With AIDS-Related Kaposi’s Sarcoma The safety data described is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma (KS) enrolled in four open-label, uncontrolled trials of doxorubicin hydrochloride liposome injection administered at doses ranging from 10 to 40 mg/m2every 2 to 3 weeks. Demographics of the population were: median age 38.7 years (range 24 to 70); 99% male; 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2of doxorubicin hydrochloride liposome injection every 2 to 3 weeks with a median exposure of 4.2 months (range 1 day to 26.6 months). The median cumulative dose was 120 mg/m2(range 3.3 to 798.6 mg/m2); 3% received cumulative doses of greater than 450 mg/m2.

*This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. **This includes only subjects with AIDS-KS who had available data from the 4 pooled trials.

*This includes a subset of subjects who were retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least 2 cycles of a regimen containing at least 2 of 3 treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy.

**This includes only subjects with AIDS-KS who had available adverse event data from the 4 pooled trials.

The following additional adverse reactions were observed in 705 patients with AIDS-related Kaposi’s sarcoma.

The safety data described are from 318 patients treated with doxorubicin hydrochloride liposome injection (30 mg/m2) administered on day 4 following bortezomib (1.3 mg/m2i.v. bolus on days 1, 4, 8 and 11) every 3 weeks, in a randomized, open-label, multicenter study (Trial 6). In this trial, patients in the doxorubicin hydrochloride liposome injection + bortezomib combination group were treated for a median number of 4.5 months (range 21 days to 13.5 months). The population was 28 to 85 years of age (median age 61), 58% male, 90% Caucasian, 6% Black, and 4% Asian and Other. Table 7 lists adverse reactions reported in 10% or more of patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma.

6.2 Postmarketing Experience

The following additional adverse reactions have been identified during postapproval use of doxorubicin hydrochloride liposome injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 DRUG INTERACTIONS

No formal drug interaction studies have been conducted with doxorubicin hydrochloride liposome injection.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Based on findings in animals and its mechanism of action, doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman; avoid the use of doxorubicin hydrochloride liposome injection during the 1st trimester. In animal reproduction studies, doxorubicin hydrochloride liposome injection was embryotoxic in rats and abortifacient in rabbits following intravenous administration during organogenesis at doses approximately 0.12 times the recommended clinical dose (see Data). Available human data do not establish the presence or absence of major birth defects and miscarriage related to the use of doxorubicin hydrochloride during the 2nd and 3rd trimesters. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated populations are unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

8.2 Lactation

Risk Summary

It is not known whether doxorubicin hydrochloride liposome injection is present in human milk. Because many drugs, including anthracyclines, are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from doxorubicin hydrochloride liposome injection, discontinue breastfeeding during treatment with doxorubicin hydrochloride liposome injection.

8.3 Females and Males of Reproductive Potential

Doxorubicin hydrochloride liposome injection can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during and for 6 months after treatment with doxorubicin hydrochloride liposome injection.

Females In females of reproductive potential, doxorubicin hydrochloride liposome injection may cause infertility and result in amenorrhea. Premature menopause can occur with doxorubicin hydrochloride. Recovery of menses and ovulation is related to age at treatment.

Males

Doxorubicin hydrochloride liposome injection may result in oligospermia, azoospermia, and permanent loss of fertility. Sperm counts have been reported to return to normal levels in some men. This may occur several years after the end of therapy [see Non-clinical Toxicology (13.1)].

8.4 Pediatric Use

The safety and effectiveness of doxorubicin hydrochloride liposome injection in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of doxorubicin hydrochloride liposome injection conducted in patients with either epithelial ovarian cancer (Trial 4) or with AIDS-related Kaposi’s sarcoma (Trial 5) did not contain sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.

In Trial 6, of 318 patients treated with doxorubicin hydrochloride liposome injection in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

8.6 Hepatic Impairment

The pharmacokinetics of doxorubicin hydrochloride liposome injection has not been adequately evaluated in patients with hepatic impairment. Doxorubicin is eliminated in large part by the liver. Reduce doxorubicin hydrochloride liposome injection for serum bilirubin of 1.2 mg/dL or higher.

10 OVERDOSAGE

11 DESCRIPTION

Doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride , an anthracycline topoisomerase inhibitor, that is encapsulated in PEGYLATEDliposomes for intravenous use.

The chemical name of doxorubicin hydrochloride is (8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxohexopyranosyl)oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The molecular formula is C27 H29 NO11•HCl; its molecular weight is 579.99.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The active ingredient of doxorubicin hydrochloride liposome injection is doxorubicin hydrochloride. The mechanism of action of doxorubicin hydrochloride is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.

12.3 Pharmacokinetics

The pharmacokinetic parameters for total doxorubicin following a single-dose of doxorubicin hydrochloride liposome injection infused over 30 minutes are presented in Table 8.

Doxorubicin hydrochloride liposome injection displayed linear pharmacokinetics over the range of 10 to 20 mg/m2. Relative to doxorubicin hydrochloride liposome injection doses at or below 20 mg/m2, the pharmacokinetics of total doxorubicin following a 50 mg/m2doxorubicin hydrochloride liposome injection dose are nonlinear. At this dose, the elimination half-life of doxorubicin hydrochloride liposome injection is longer and the clearance lower compared to a 20 mg/m2dose.

Distribution:

Direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5 to 10% free doxorubicin) remains liposome-encapsulated during circulation.

In contrast to doxorubicin, which displays a large volume of distribution (range 700 to 1100 L/m2), the small steady state volume of distribution of liposomal doxorubicin suggests that doxorubicin hydrochloride liposome injection is largely confined to vascular fluid. Doxorubicin becomes available after the liposomes are extravasated. Plasma protein binding of doxorubicin hydrochloride liposome injection has not been determined; the plasma protein binding of doxorubicin is approximately 70%.

Metabolism:

Doxorubicinol, the major metabolite of doxorubicin, was detected at concentrations of 0.8 to 26.2 ng/mL in the plasma of patients who received 10 or 20 mg/m2doxorubicin hydrochloride liposome injection.

Elimination:

The plasma clearance of total doxorubicin from doxorubicin hydrochloride liposome injection was 0.041 L/h/m2at a dose of 20 mg/m2. Following administration of doxorubicin hydrochloride, the plasma clearance of doxorubicin is 24 to 35 L/h/m2.

13 NON-CLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis,and Impairment of Fertility

Mutagenicity or carcinogenicity studies have not been conducted with doxorubicin hydrochloride liposome injection, however doxorubicin was shown to be mutagenic in the in vitro Ames assay, and clastogenic in multiple in vitro assays (CHO cell, V79 hamster cell, human lymphoblast, and SCE assays) and the in vivo mouse micronucleus assay. The possible adverse effects on fertility in animals have not been adequately evaluated. Doxorubicin hydrochloride liposome injection resulted in mild to moderate ovarian and testicular atrophy in mice after administration of a single dose of 36 mg/kg (about 2 times the 50 mg/m2human dose on a mg/m2basis). Decreased testicular weights and hypospermia were observed in rats after repeat doses ≥ 0.25 mg/kg/day (about 0.03 times the 50 mg/m2human dose on a mg/m2basis), and diffuse degeneration of the seminiferous tubules and a marked decrease in spermatogenesis were observed in dogs after repeat doses of 1 mg/kg/day (about 0.4 times the 50 mg/m2human dose on a mg/m2basis).

14 CLINICAL STUDIES

14.1 Ovarian Cancer

Doxorubicin hydrochloride liposome injection was studied in three open-label, single-arm, clinical studies of 176 patients with metastatic ovarian cancer (Trials 1, 2, and 3). One hundred forty-five of these patients were refractory to both paclitaxel-and platinum-based chemotherapy regimens, defined as disease progression while on treatment or relapse within 6 months of completing treatment. Patients received doxorubicin hydrochloride liposome injection at 50 mg/m2every 3 or 4 weeks for 3 to 6+ cycles in the absence of dose-limiting toxicity or disease progression.

The median age at diagnosis ranged from 52 to 64 years in the 3 studies, and the range was 22 to 85. Most patients had International Federation of Obstetricians and Gynecologists (FIGO) stage III or IV disease (ranging from 83% to 93%). Approximately one third of the patients had three or more prior lines of therapy (ranging from 22% to 33%).

The primary outcome measure was confirmed response rate based on Southwestern Oncology Group (SWOG) criteria for patients refractory to both paclitaxel-and a platinum-containing regimen. Secondary efficacy parameters were time to response, duration of response, and time to progression.

The response rates for the individual single arm trials are given in Table 9 below.

In a pooled analysis of Trials 1 to 3, the response rate for all patients refractory to paclitaxel and platinum agents was 13.8% (95% CI 8.1% to 19.3%). The median time to progression was 15.9 weeks, the median time to response was 17.6 weeks, and the duration of response was 39.4 weeks.

In Trial 4, a randomized, multicenter, open-label, trial in 474 patients with epithelial ovarian cancer after platinum-based chemotherapy, patients were randomized to receive either doxorubicin hydrochloride liposome injection 50 mg/m2every 4 weeks (n=239) or topotecan 1.5 mg/m2daily for 5 consecutive days every 3 weeks (n=235). Patients were stratified according to platinum sensitivity (response to initial platinum-based therapy and a progression-free interval of greater than 6 months off treatment) and the presence of bulky disease (tumor mass greater than 5 cm in size). The primary outcome measure was time to progression (TTP). Other endpoints included overall survival and objective response rate.

Of the 474 patients, the median age at diagnosis was 60 years (range 25 to 87), 90% were FIGO stage III and IV; 46% were platinum sensitive; and 45% had bulky disease. There was no statistically significant difference in TTP between the two arms. Results are provided in Table 10.

1 1 Analysis based on investigators’ strata for protocol defined ITT population. 2 Kaplan-Meier estimates. 3 p-value is based on the stratified log-rank test. 4Hazard ratio is based on Cox proportional-hazard model with the treatment as single independent variable. A hazard ratio less than 1 indicates an advantage for doxorubicin hydrochloride liposome injection. 5 p-value not adjusted for multiple comparisons.

14.2 AIDS-Related Kaposi’s Sarcoma

Doxorubicin hydrochloride liposome injection was studied in an open-label, single-arm, multicenter study at a dose of 20 mg/m2every 3 weeks, until disease progression or unacceptable toxicity (Trial 5). Data is described for a cohort of 77 patients retrospectively identified as having disease progression on prior systemic combination chemotherapy (at least two cycles of a regimen containing at least two of three treatments: bleomycin, vincristine or vinblastine, or doxorubicin) or as being intolerant to such therapy. Forty-nine of the 77 (64%) patients had received prior doxorubicin hydrochloride.

The median time on study was 5.1 months (range 1 day to 15 months). The median cumulative dose of doxorubicin hydrochloride liposome injection was 154 mg/m2(range 20 to 620 mg/m2). Among the 77 patients, mean age was 38 years (range 24 to 54); 87% were Caucasian, 5% Hispanic, 4% Black, and 4% Asian/Other/Unknown; median CD4 count was 10 cells/mm3; ACTG staging criteria were 78% poor risk for tumor burden, 96% poor risk for immune system, and 58% poor risk for systemic illness at baseline; and mean Karnofsky status score was 74%. All patients had cutaneous or subcutaneous lesions, 40% also had oral lesions, 26% pulmonary lesions, and 14% had lesions of the stomach/intestine.

Two analyses of tumor response were used: one based on investigator assessment of changes in lesions based on modified ACTG criteria (partial response defined as no new lesions, sites of disease, or worsening edema; flattening of ≥50% of previously raised lesions or area of indicator lesions decreasing by ≥50%; and response lasting at least 21 days with no prior progression), and one based on changes in up to five prospectively indentified representative indicator lesions (partial response defined as flattening of ≥50% of previously raised indicator lesions, or >50% decrease in the area of indicator lesions and lasting at least 21 days with no prior progression). Of the 77 patients, 34 were evaluable for investigator assessment and 42 were evaluable for indicator lesion assessment; analyses of tumor responses are shown in Table 11.

1 Patients with disease that progressed on prior combination chemotherapy or who were intolerant to such therapy.

2 There were no complete responses in this population.

Retrospective efficacy analyses were performed in two trials that had subsets of patients who received single-agent doxorubicin hydrochloride liposome injection and who were on stable antiretroviral therapy for at least 60 days prior to enrollment and until a response was demonstrated. In one trial, 7 of 17 (40%) patients had a durable response (median duration not reached but was longer than 11.6 months). In the second trial, 4 of 11 patients (40%) on a stable antiretroviral therapy demonstrated durable responses.

14.3 Multiple Myeloma

The efficacy of doxorubicin hydrochloride liposome injection in combination with bortezomib was evaluated in Trial 6, a randomized, open-label, international, multicenter study in 646 patients who had not previously received bortezomib and whose disease progressed during or after at least one prior therapy. Patients were randomized (1:1) to receive either doxorubicin hydrochloride liposome injection (30 mg/m2) administered IV on day 4 following bortezomib (1.3 mg/m2IV on days 1, 4, 8 and 11) or bortezomib alone every 3 weeks for up to 8 cycles or until disease progression or unacceptable toxicity. Patients who maintained a response were allowed to receive further treatment. The median number of cycles in each treatment arm was 5 (range 1 to 18).

The baseline demographics and clinical characteristics of the patients with multiple myeloma were similar between treatment arms (Table 12).

Table 12: Summary of Baseline Patient and Disease Characteristics

Patient Characteristics

Doxorubicin Hydrochloride Liposome Injection+bortezomibn=324

bortezomibN=322

Median age in years (range)

61 (28, 85)

62 (34, 88)

% Male/female

58 / 42

54 / 46

% Caucasian/Black/other

90 / 6/ 4

94 / 4 / 2

Disease Characteristics

% with IgG/IgA/Light chain

57 / 27 / 12

62 / 24 /11

% β2 -microglobulin group

≤2.5 mg/L

14

14

>2.5 mg/L and ≤5.5 mg/L

56

55

>5.5 mg/L

30

31

Serum M-protein (g/dL): Median (Range)

2.5 (0 to10)

2.7 (0 to 10)

Urine M-protein (mg/24 hours): Median (Range)

107 (0 to 24883)

66 (0 to 39657)

Median Months Since Diagnosis

35.2

37.5

% Prior Therapy

One

34

34

More than one

66

66

Prior Systemic Therapies for Multiple Myeloma

Corticosteroid (%)

99

>99

Anthracyclines

68

67

Alkylating agent (%)

92

90

Thalidomide/lenalidomide (%)

40

43

Stem cell transplantation (%)

57

54

The primary outcome measure was time to progression (TTP). TTP was defined as the time from randomization to the first occurrence of progressive disease or death due to progressive disease. The combination arm demonstrated significant improvement in TTP. As the prespecified primary objective was achieved at the interim analysis, patients in the bortezomib monotherapy group were then allowed to receive the doxorubicin hydrochloride liposome injection + bortezomib combination. Efficacy results are as shown in Table 13 and Figure 1.

Table 13: Efficacy of Doxorubicin Hydrochloride Liposome Injection in Combination With Bortezomib in the Treatment of Patients With Multiple Myeloma

At the final analysis of survival, 78% of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had died after a median follow up of 8.6 years. The median survival was 33 months in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 31 months in the bortezomib monotherapy group. There was no difference observed in overall survival at the final analysis [HR for doxorubicin hydrochloride liposome injection + bortezomib vs. bortezomib= 0.96 (95% CI 0.80, 1.14)].

Seventy-eight percent of subjects in the doxorubicin hydrochloride liposome injection and bortezomib combination therapy group and 80% of subjects in the bortezomib monotherapy group had received subsequent therapy.

17 PATIENT COUNSELING INFORMATION

Cardiomyopathy Advise patients to contact their healthcare provider if they develop symptoms of heart failure [see Warnings and Precautions (5.1)]. Infusion-Related Reactions Advise patients about the symptoms of infusion related reactions and to seek immediate medical attention if they develop any of these symptoms [see Warnings and Precautions (5.2)].

Myelosuppression Advise patients to contact their healthcare provider for a new onset fever or symptoms of infection. Hand-Foot Syndrome Advise patients to notify their healthcare provider if they experience tingling or burning, redness, flaking, bothersome swelling, small blisters, or small sores on the palms of their hands or soles of their feet (symptoms of Hand-Foot Syndrome) [see Warnings and Precautions (5.3)]. Stomatitis Advise patients to notify their healthcare provider if they develop painful redness, swelling, or sores in the mouth (symptoms of stomatitis).

Embryofetal Toxicity Advise females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.5) and Use in Specific Populations (8.1)].

Advise females and males of reproductive potential to use effective contraception during and for 6 months following treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.3)].

Lactation Advise females not to breastfeed during treatment with doxorubicin hydrochloride liposome injection [see Use in Specific Populations (8.2)].

Discoloration of Urine and Body Fluids Inform patients that following doxorubicin hydrochloride liposome injection administration, a reddish-orange color to the urine and other body fluids may be observed. This nontoxic reaction is due to the color of the product and will dissipate as the drug is eliminated from the body.